The Bmi-1 gene was originally identified by its over-expression in various lymphomas. Subsequently, Bmi-1 has been shown to have oncogenic activity when over-expressed in normal cells and to play a role in maintenance of adult stem cell populations (asymmetric cell division). The Bmi-1 protein is elevated in many tumor types and is particularly important in hematologic cancers and brain cancers. Experimental reduction of Bmi-1 protein levels by siRNA causes apoptosis and/or cell senescence in tumor cells in vitro and increases their susceptibility to cytotoxic agents such as 5-fluorouracil. The Bmi-1 protein has no enzymatic activity, but serves as the key regulatory component of the PRC1 complex (polycomb repressive complex-1). As a nonenzymatic but key regulatory member of the PRC1 complex, targeting Bmi-1 by traditional drug discovery methods is problematic. Bmi-1 protein levels are tightly regulated within cells through both transcriptional and post-transcriptional mechanisms.
Accordingly, there still remains a need for anticancer drugs that effect tumor regulatory mechanisms with reduced side effects.